Circulating human sPRR increased blood pressure in female mice fed a low‐fat diet

Abstract

Essential hypertension and obesity‐hypertension have been associated with elevated plasma soluble prorenin receptor (sPRR) in men. Additionally, our laboratory previously found that the infusion of mouse sPRR elevates systolic blood pressure (SBP) in high‐fat (HF) fed male mice through activation of the sympathetic nervous system but did not elevate SBP in HF‐fed female mice. Interestingly, the infusion of mouse sPRR increased renal and hepatic angiotensinogen (AGT) and plasma renin concentration in female mice fed a standard diet. However, the mechanistic role of sPRR on the renin angiotensin system (RAS) to regulate blood pressure in lean female mice remains to be investigated. Moreover, there is critical gap concerning the functional role of human sPRR on blood pressure in women. Therefore, in the present study, we aim to determine whether human sPRR participates to blood pressure control in lean female mice.A transgenic mouse model expressing the human form of the soluble prorenin receptor (HsPRR‐Myc‐tag) was developed. Human sPRR‐transgenic female mice were bred with male mice expressing Alb/Cre recombinase to generate mice selectively expressing human sPRR (Alb‐HsPRR) in the liver and control littermates (CTL). Control and Alb‐HsPRR female mice were fed a LF‐diet for 8 months (n=11/groups). Body weight was assessed weekly and body composition was examined monthly. Blood pressure was assessed by radiotelemetry. Human sPRR‐Myc‐tag was detected in the liver of Alb‐HsPRR female mice and plasma sPRR levels increased by 50‐fold (CTL: 3.6±0.5 ng/ml, Alb‐HsPRR: 190.5±24.4 ng/ml; P<0.05), which validated the humanized mouse model.Elevated circulating human sPRR did not change body weight (CTL: 22.2±0.4g, Alb‐HsPRR: 23.0±0.3g) or fat mass (CTL: 2.5±0.2, Alb‐HsPRR:3.1±0.2g). Liver‐derived human sPRR significantly elevated SBP in Alb‐HsPRR compared to control female mice (Night SBP: CTL, 130.5±1.2 mmHg; Alb‐HsPRR, 135.9±2 mmHg; P<0.05) and acute injection of Angiotensin II exacerbated the SBP elevation. Interestingly, the decrease in blood pressure mediated by Losartan was not different between Alb‐HsPRR and control female mice (Night □SBP: CTL, ‐13.1±2.2 mmHg; Alb‐HsPRR, ‐14.8±2.7 mmHg; P>0.05). Plasma AGT and renin activity were similar between Alb‐HsPRR and control littermate female mice suggesting that the elevation of SBP was not mediated by the circulating renin angiotensin system. Therefore, whether the sympathetic nervous system is involved in human sPRR‐mediated increase of SBP remains to be examined. Altogether, these results support an important role of circulating human sPRR in blood pressure control in women.